BackgroundRandomized controlled trials (RCTs) are often complex and expensive to perform. Less than one third achieve planned recruitment targets, follow-up can be labor-intensive, and many have limited real-world generalizability. Designs for RCTs conducted using cohorts and routinely collected health data, including registries, electronic health records, and administrative databases, have been proposed to address these challenges and are being rapidly adopted. These designs, however, are relatively recent innovations, and published RCT reports often do not describe important aspects of their methodology in (...) a standardized way. Our objective is to extend the Consolidated Standards of Reporting Trials (CONSORT) statement with a consensus-driven reporting guideline for RCTs using cohorts and routinely collected health data.MethodsThe development of this CONSORT extension will consist of five phases. Phase 1 (completed) consisted of the project launch, including fundraising, the establishment of a research team, and development of a conceptual framework. In phase 2, a systematic review will be performed to identify publications (1) that describe methods or reporting considerations for RCTs conducted using cohorts and routinely collected health data or (2) that are protocols or report results from such RCTs. An initial “long list” of possible modifications to CONSORT checklist items and possible new items for the reporting guideline will be generated based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statements. Additional possible modifications and new items will be identified based on the results of the systematic review. Phase 3 will consist of a three-round Delphi exercise with methods and content experts to evaluate the “long list” and generate a “short list” of key items. In phase 4, these items will serve as the basis for an in-person consensus meeting to finalize a core set of items to be included in the reporting guideline and checklist. Phase 5 will involve drafting the checklist and elaboration-explanation documents, and dissemination and implementation of the guideline.DiscussionDevelopment of this CONSORT extension will contribute to more transparent reporting of RCTs conducted using cohorts and routinely collected health data. (shrink)

We tested the hypothesis that choices determined by Type 1 processes are compelling because they are fluent, and for this reason they are less subject to analytic thinking than other answers. A total of 104 participants completed a modified version of Wason's selection task wherein they made decisions about one card at a time using a two-response paradigm. In this paradigm participants gave a fast, intuitive response, rated their feeling of rightness for that response, and were then allowed free time (...) to reconsider their answers. As we predicted, answers consistent with a matching heuristic were made more quickly than other answers, were given higher FOR ratings, and received less subsequent analysis as measured by rethinking time and the probability of changing answers. These data suggest that reasoning biases may be compelling because they are fluently generated; this is turn creates a strong FOR, which acts as a signal that further analysis is not necessary. (shrink)

C. A. Campbell has for many years defended vigorously, and often persuasively, the following libertarian claims: that the libertarian concept of freedom of choice is meaningful; that the libertarian variety of freedom of choice is necessary for moral responsibility; and that the libertarian variety of freedom of choice is a reality. This paper will be concerned with Campbell's effort of will argument for the last claim.

This case describes an adolescent in a crisis of a chronic medical condition whose situation is complicated by substance abuse and mental illness. D. Micah Hester provides an analytic approach, teasing apart the multiple layers of medical, developmental, and moral issues at hand and describing possible responses and outcomes. Amy T. Campbell examines existing legal guidelines for adolescent decision making, arguing that greater space exists for clinical discretion in these matters than commonly thought. Cheryl D. Lew discusses the development (...) of agency in adolescent patients, the ideal of autonomous decision making in the context of impairment and chronic illness, and the obligation of healthcare teams to examine an adolescent patient’s decisions in relation to her identity. (shrink)

Background: Omalizumab, an anti-immunoglobulin E antibody, reduces exacerbations and symptoms in uncontrolled allergic asthma. The study objective was to estimate the costs and consequences of omalizumab compared to usual care from a US payer perspective. Methods: We estimated payer costs, quality-adjusted survival (QALYs), and the incremental cost-effectiveness ratio (ICER) of omalizumab compared to usual care using a state-transition simulation model that included sensitivity analyses. Every 2 weeks, patients could transition between chronic asthma and exacerbation health states. The best available evidence (...) informed the clinical and cost input estimates. Five years of omalizumab treatment followed by usual care was assumed to estimate a lifetime horizon. Omalizumab responders (60.5% of treated) were modeled as a separate scenario where nonresponders reverted back to usual care after 16 weeks of active treatment. Results: The mean lifetime discounted costs and QALYs were $83 400 and 13.87 for usual care and $174 500 and 14.19 for omalizumab plus usual care resulting in $287 200/QALY (95% interval: $219 300, $557 900). The ICER was $172 300/QALY when comparing omalizumab to usual care in the responder scenario. One-way sensitivity analyses indicated that the results were sensitive to the difference in treatment-specific utilities for the chronic state, exacerbation-associated mortality, omalizumab price, exacerbation rates, and response definition. Conclusions: The results suggest that adding omalizumab to usual care improves QALYs at an increase in direct medical costs. The cost-effectiveness of omalizumab is similar to other chronic disease biologics. The value increases when omalizumab response is used to guide long-term treatment. (shrink)

Fractal geometry offers a new approach to describing the morphology of fern leaves. Traditional morphology is based on the Euclidean concept of shape as an area defined by a boundary. This approach has not proven successful with fern leaves because they are so elaborate. Fractal geometry treats forms as relationships between parts rather than as areas. In fern fronds there are often constant relationships between parts. Four fractal methodologies for describing these relations within leaves are explored in this paper. These (...) include recursive line branching algorithms, iterated function systems (IFS), modifications of IFS, and L-systems. The methods are evaluated by comparing their results with measurements and appearances of various ferns. Fractal methods offer objective, quantifiable and succinct descriptions of fern-leaves. We conclude that fractal geometry offers simple descriptions of some elaborate fern shapes and that it will probably have application in investigating different aspects of ferns and other organisms. (shrink)

Nanomedicine is yielding new and improved treatments and diagnostics for a range of diseases and disorders. Nanomedicine applications incorporate materials and components with nanoscale dimensions where novel physiochemical properties emerge as a result of size-dependent phenomena and high surface-to-mass ratio. Nanotherapeutics and in vivo nanodiagnostics are a subset of nanomedicine products that enter the human body. These include drugs, biological products, implantable medical devices, and combination products that are designed to function in the body in ways unachievable at larger scales. (...) Nanotherapeutics andin vivonanodiagnostics incorporate materials that are engineered at the nanoscale to express novel properties that are medicinally useful. These nanomedicine applications can also contain nanomaterials that are biologically active, producing interactions that depend on biological triggers. Examples include nanoscale formulations of insoluble drugs to improve bioavailability and pharmacokinetics, drugs encapsulated in hollow nanoparticles with the ability to target and cross cellular and tissue membranes and to release their payload at a specific time or location, imaging agents that demonstrate novel optical properties to aid in locating micrometastases, and antimicrobial and drug-eluting components or coatings of implantable medical devices such as stents. (shrink)

Using a longitudinal case study design, we have tracked the recovery of motor function following severe traumatic brain injury (TBI) through a multimodal neuroimaging approach. In 2006, Canadian Soldier Captain (retired) Trevor Greene (TG) was attacked with an axe to the head while on tour in Afghanistan. TG continues intensive daily rehabilitation, which recently included the integration of physical therapy (PT) with neuromodulation using translingual neurostimulation (TLNS) to facilitate neuroplasticity. Recent findings with PT+TLNS demonstrated that recovery of motor function occurred (...) beyond conventional time limits, currently extending past 14-years post-injury. To investigate whether PT+TLNS similarly resulted in associated cognitive function improvements, we examined event-related potentials (ERPs) with the brain vital signs framework. In parallel with motor function improvements, brain vital signs detected significant increases in basic attention (as measured by P300 response amplitude) and cognitive processing (as measured by contextual N400 response amplitude). These objective cognitive improvements corresponded with TG’s self-reported improvements, including a noteworthy and consistent reduction in ongoing symptoms of post-traumatic stress disorder (PTSD). The findings provide valuable insight into the potential importance of non-invasive neuromodulation in cognitive rehabilitation, in addition to initial indications for physical rehabilitation. (shrink)

Class inclusion theory asserts that one cannot reverse the topic and vehicle of a metaphor and produce a new, meaningful metaphor that is based on the same interpretive ground. In 2 experiments we test that claim. In Study 1 we replicate the procedures employed by Glucksberg, McGlone, & Manfredi (1997) that provided support for the assertion. However we now add experimental conditions in which the target metaphors, either with the topic and vehicle in its canonical order or reversed, are placed (...) in discourse contexts that provide support for a meaningful interpretation based on the same ground. In contrast to the prediction of class inclusion theory, fully 72% of the cases the reversed metaphors were rated as interpretable and interpretation was based on the same ground used in interpreting the metaphors in their canonical order. In Study 2, the online processing of the metaphors in context are examined in a word-by-word reading task. We find that canonical and reversed order metaphors were read at the same rate throughout and both sets exhibited the same reading patterns: increased reading time of the noun-phrase (NP) that contains the metaphoric vehicle and of the first word in the text that follows the metaphor. We take these data to indicate that nonreversibility cannot be taken as a necessary condition of metaphor. (shrink)

Editors of Pliny's Naturalis Historia have not had to deplore the paucity of the MS. tradition, but rather its value; while MSS. belonging to the ordo recentiorum are numerous and fairly complete, those of the ordo uetustiorum are very few, and never contain more than a few books, often with considerable gaps. They are A ii 196–vi 51, M xi–xv, P and H parts of xviii, I xxiii, xxv, B xxxii–xxxvii . There are also some scattered fragments. Detlefsen indeed claimed (...) that the restoration of the original text of the N.H. is more difficult than that of any other Latin author owing to the mutilated and defective transmission of considerable parts. (shrink)

Editors of Pliny's Naturalis Historia have not had to deplore the paucity of the MS. tradition, but rather its value; while MSS. belonging to the ordo recentiorum are numerous and fairly complete, those of the ordo uetustiorum are very few, and never contain more than a few books, often with considerable gaps. They are A ii 196–vi 51, M xi–xv, P and H parts of xviii, I xxiii, xxv, B xxxii–xxxvii. There are also some scattered fragments. Detlefsen indeed claimed that (...) the restoration of the original text of the N.H. is more difficult than that of any other Latin author owing to the mutilated and defective transmission of considerable parts. (shrink)

Randomized controlled trial trial designs exist on an explanatory-pragmatic spectrum, depending on the degree to which a study aims to address a question of efficacy or effectiveness. As conceptualized by Schwartz and Lellouch in 1967, an explanatory approach to trial design emphasizes hypothesis testing about the mechanisms of action of treatments under ideal conditions, whereas a pragmatic approach emphasizes testing effectiveness of two or more available treatments in real-world conditions. Interest in, and the number of, pragmatic trials has grown substantially (...) in recent years, with increased recognition by funders and stakeholders worldwide of the need for credible evidence to inform clinical decision-making. This increase has been accompanied by the onset of learning healthcare systems, as well as an increasing focus on patient-oriented research. However, pragmatic trials have ethical challenges that have not yet been identified or adequately characterized. The present study aims to explore the views of key stakeholders with respect to ethical issues raised by the design and conduct of pragmatic trials. It is embedded within a large, four-year project that seeks to develop guidance for the ethical design and conduct of pragmatic trials. As a first step, this study will address important gaps in the current empirical literature with respect to identifying a comprehensive range of ethical issues arising from the design and conduct of pragmatic trials. By opening up a broad range of topics for consideration within our parallel ethical analysis, we will extend the current debate, which has largely emphasized issues of consent, to the range of ethical considerations that may flow from specific design choices. Semi-structured interviews with key stakeholders, across multiple jurisdictions, identified based on their known experience and/or expertise with pragmatic trials. We expect that the study outputs will be of interest to a wide range of knowledge users including trialists, ethicists, research ethics committees, journal editors, regulators, healthcare policymakers, research funders and patient groups. All publications will adhere to the Tri-Agency Open Access Policy on Publications. (shrink)

Imaginative resistance refers to cases in which one’s otherwise flexible imaginative capacity is constrained by an unwillingness or inability to imaginatively engage with a given claim. In three studies, we explored which specific imaginative demands engender resistance when imagining morally deviant worlds and whether individual differences in emotion predict the degree of this resistance. In Study 1 (N = 176), participants resisted the notion that harmful actions could be morally acceptable in the world of a narrative regardless of the author’s (...) claims about these actions but did not resist imagining that a perpetrator of harm could believe their actions to be morally acceptable. In Study 2 (N = 167) we replicated the findings of Study 1 and showed that imaginative resistance is greatest among participants who experience more negative affect in response to imagining harm and are lower in either trait anxiety or trait psychopathy. In Study 3 (N = 210) we show that this is the case even when the harms assessed include both low-severity (i.e., emotional harm) and high-severity (i.e., killing) cases. Thus, people’s moral beliefs constrain their ability to imagine hypothetical moral alternatives, although this ability systematically varies on the basis of stable individual differences in emotion. (shrink)

As fundamental researchers in the neuroethology of efference copy, we were stimulated by Grush's bold and original synthesis. In the following critique, we draw attention to ways in which it might be tested in the future, we point out an avoidable conceptual error concerning emulation that Grush seems to share with other workers in the field, and we raise questions about the neural correlates of Grush's schemata that might be probed by neurophysiologists.